Process for producing optically active carboxylic acid subtituted in 2-position

ABSTRACT

A nitrous acid salt is added at a temperature of 10 to 80° C. to an aqueous solution which contains an optically active 2-aminocarboxylic acid (4) and a protonic acid, the amount of the latter acid being 1 to 3 equivalents to the former, and which has a proton concentration of 0.5 to 2 mol/kg to conduct a reaction to thereby produce an optically active 2-hydroxycarboxylic acid (1). Thionyl chloride and a basic compound are caused to act on the compound (1) to chlorinate it and simultaneously invert the configuration in the 2-position. Thus, an optically active 2-chlorocarboxylic acid chloride (5) is induced. The compound (5) is hydrolyzed to induce an optically active 2-chlorocarboxylic acid (2). The compound (2) is reacted with a thioacetic acid salt to incorporate an acetylthio group thereinto and simultaneously invert the configuration in the 2-position to thereby produce an optically active 2-acetylthiocarboxylic acid (3).

TECHNICAL FIELD

[0001] The present invention relates to a method of producing opticallyactive 2-hydroxycarboxylic acids, optically active 2-chlorocarboxylicacids and optically active 2-acetylthiocarboxylic acids, which areimportant as intermediates for the production of pharmaceuticals and soforth.

BACKGROUND ART

[0002] Optically active 2-hydroxycarboxylic acids represented by thegeneral formula (1):

[0003] (wherein R¹ represents a substituted or unsubstituted alkyl groupcontaining 1 to 12 carbon atoms, a substituted or unsubstituted arylgroup containing 6 to 14 carbon atoms or a substituted or unsubstitutedaralkyl group containing 7 to 15 carbon atoms) are importantintermediates in the production of pharmaceuticals (for example, Biosci.Biotech. Biochem., 60 (8), 1279-1283, 1996) and, for the productionthereof, the following methods are known, among others:

[0004] (i) L-Phenylalanine hydrochloride is prepared by treatingL-phenylalanine with concentrated hydrochloric acid in chloroform and,then, (2S)-2-hydroxy-3-phenylpropionic acid is synthesized by treatingan aqueous solution (proton concentration 1.4 mol/kg) containingL-phenylalanine and 4 equivalents, relative to L-phenylalanine, of aprotonic acid (hydrochloric acid and sulfuric acid) with an aqueoussolution containing 2 moles of sodium nitrite per mole ofL-phenylalanine at 0° C. for 3 hours. After the reaction, the(2S)-2-hydroxy-3-phenylpropionic acid is recovered as crystals by etherextraction, dehydration, ether extract concentration and treatment ofthe residue with benzene (isolation yield 40%) (J. Amer. Chem. Soc., 86,5326-5330, 1964);

[0005] (ii) (2S)-2-Hydroxy-3-phenylpropionic acid is synthesized byadding 4 moles, per mole of L-phenylalanine, of solid sodium nitrite toan aqueous solution (proton concentration 2.1 mol/kg) containingL-phenylalanine and 4 equivalents, relative to L-phenylalanine, of aprotonic acid (sulfuric acid) at 0° C. over 5 hours, gradually warmingthe mixture to room temperature and stirring the same overnight. Afterthe reaction, the (2S)-2-hydroxy-3-phenylpropionic acid is recovered ascrystals by two or more times of extraction with ethyl acetate, washingof the extract with a saturated aqueous solution of sodium chloride,dehydration of the same over magnesium sulfate, concentration of theethyl acetate solution and crystallization by addition of hexane(isolation yield 50%) (J. Heterocyclic Chem., 29, 431-438, 1992).

[0006] However, check experiments made by the present inventorsconcerning the above method (i) revealed that the method has suchproblems as the use of chloroform and benzene, which are highly toxicorganic solvents, and the very low reaction yield (42%).

[0007] Checking of the above method (ii) by experiment revealed suchproblems as procedure complicatedness and increased capacityrequirement, as resulting from the use of solid sodium nitrite and oflarge amounts of organic solvents and inorganic salts. It was alsorevealed that the reaction yield itself is low, namely 65%. In Biosci.Biotech. Biochem., 60 (8), 1279-1283, 1996, it is noted to the effectthat the above method (ii) allows the formation, as a byproduct, of alarge amount of a related substance (cinnamic acid) and accordinglygives a low yield, hence it is very difficult to employ that method on acommercial scale.

[0008] Further, it was revealed that the above methods (i) and (ii)still have another problem in that the optical purity is reduced by theformation of a considerable amount of the optical isomer(2R)-2-hydroxy-3-phenylpropionic acid as a byproduct as a result ofracemization.

[0009] With such a background, alternative methods of producingoptically active 2-hydroxy-3-phenylpropionic acid have been made, forexample the method comprising asymmetric reduction of racemic2-hydroxy-3-phenylpropionitrile using a microorganism (e.g. Biosci.Biotech, Biochem., 60 (8), 1279-1283, 1996 and JP-A 6-237789). Thesemethod are, however, not entirely favorable since the cyano compound tobe used is highly toxic, the productivity is low and, further, nosatisfactory optical purity can be obtained.

[0010] As for the production of optically active carboxylic acidssubstituted by a chlorine atom in the 2-position, which are representedby the general formula (2):

[0011] (wherein R¹ is as defined above) the following are known in theart:

[0012] (i) The method comprising using an amino acid as a startingmaterial and chlorinating the same using sodium nitrite while retainingthe configuration thereof (Liebigs Ann., 1907, 357, 1); and

[0013] (ii) The method comprising chlorinating a 2-hydroxycarboxylicacid ester with configurational inversion (JP-A 61-57534).

[0014] However, the method (i) indeed gives a 2-chlorocarboxylic acidwhose configuration at 2-position is (S) when a naturally occurringL-amino acid is used as the starting material but, for producing a2-chlorocarboxylic acid whose configuration at 2-position is (R), itrequires the use of a non-natural D amino acid, which is expensive, asthe starting material, hence it has its limit as a method of producing(R)-2-chlorocarboxylic acids.

[0015] As for the method (ii), it is necessary to derivatize a2-hydroxycarboxylic acid into a 2-hydroxycarboxylic acid ester,chlorinate the same with configurational inversion and then derivatizethe chlorination product into a 2-chlorocarboxylic acid by hydrolysis.Thus, a number of steps have to be required and the method is notefficient.

[0016] Further, optically active 2-acetylthiocarboxylic acidsrepresented by the general formula (3):

[0017] (wherein R¹ is as defined above) are important intermediates inthe production of pharmaceuticals (e.g. as intermediates ofantihypertensive agents; cf. JP-A 8-337527). For the production thereof,the following are known in the art:

[0018] (i) The method comprising thioacetylating a non-natural D-aminoacid via configuration-retaining bromination (JP-A 8-337527 etc.);

[0019] (ii) The method comprising optical resolution of a racemic2-acetylthiocarboxylic acid (JP-A 6-56790);

[0020] (iii) The method comprising hydrolyzing a thiazoline compound bymeans of a microorganism (JP-A 11-192097); and

[0021] (iv) The method comprising stereoseletively reducing adi-substituted acrylic acid derivative by means of a microorganism (JP-A11-196889).

[0022] However, for producing an (S) form, the method (i) requires theuse of an expensive non-natural D-amino acid as the starting material,hence it has its limit as a method of producing (S) forms.

[0023] The method (ii) lies in optical resolution of racemic2-acetylthiocarboxylic acids, hence is not so efficient but has aproblem from the industrial utilization viewpoint.

[0024] The method (iii) requires a separate procedure for increasing theoptical purity since the 2-thiocarboxylic acid derivative obtained byhydrolysis of the thiohydantoin derivative has an optical purity as lowas 82% ee. Thus it has a problem from the industrial utilizationviewpoint.

[0025] The method (iv) is low in yield of asymmetric reduction ofmercaptoacrylic acid derivative, namely 60 to 70% and, further, the2-thiocarboxylic acid derivative obtained has an optical purity as lowas 90% ee. Thus it has problems from the industrial utilizationviewpoint.

DISCLOSURE OF INVENTION

[0026] In view of the above-mentioned state of the art, it is an objectof the present invention to produce optically active 2-hydroxycarboxylicacids, which are important for the production of pharmaceuticals andother compounds, with good operability and in high yields.

[0027] In view of the above-mentioned state of the art, it is anotherobject of the invention to isolate or purify optically active2-hydroxycarboxylic acids expediently and efficiently on a commercialscale by efficiently removing related substances and/or undesiredoptical isomers coexisting with the desired optically active2-hydroxycarboxylic acids.

[0028] In view of the above-mentioned state of the art, it is a furtherobject of the invention to produce optically active 2-chlorocarboxylicacids, which are important for the production of pharmaceuticals andother compounds, from readily available starting materials, such asL-amino acids, efficiently and in high optical purity.

[0029] In view of the above-mentioned state of the art, it is a stillfurther object of the invention to produce optically active2-acetylthiocarboxylic acids, which are important for the production ofpharmaceuticals and other compounds, from readily available startingmaterials, such as L-amino acids, efficiently and in high opticalpurity.

[0030] Thus, the present invention relates to a method of producingoptically active 2-hydroxycarboxylic acids represented by the generalformula (1):

[0031] in which R¹ represents a substituted or unsubstituted alkyl groupcontaining 1 to 12 carbon atoms, a substituted or unsubstituted arylgroup containing 6 to 14 carbon atoms or a substituted or unsubstitutedaralkyl group containing 7 to 15 carbon atoms,

[0032] by reacting an optically active 2-aminocarboxylic acidrepresented by the general formula (4):

[0033] in which R¹ is as defined above,

[0034] with a nitrite salt and a protonic acid in aqueous solution,

[0035] which method comprises carrying out the reaction by adding thenitrite salt to an aqueous solution containing said optically active2-aminocarboxylic acid and 1 to 3 equivalents, relative to the opticallyactive 2-aminocarboxylic acid, of the protonic acid and having a protonconcentration of 0.5 to 2 mol/kg at a temperature of 10 to 80° C.

[0036] The invention also relates to a method of crystallizing outoptically active 2-hydroxycarboxylic acids

[0037] which comprises causing crystallization of an optically active2-hydroxycarboxylic acid represented by the above general formula (1) byusing t-butyl methyl ether and a hydrocarbon solvent.

[0038] Further, the invention relates to a method of producing opticallyactive 2-chlorocarboxylic acid chlorides represented by the generalformula (5):

[0039] in which R¹ is as defined above,

[0040] which comprises reacting an optically active 2-hydroxycarboxylicacid represented by the above general formula (1) with thionyl chlorideand a basic compound for chlorination with inversion of theconfiguration at 2-position.

[0041] The invention also relates to a method of producing opticallyactive 2-chlorocarboxylic acids represented by the general formula (2):

[0042] in which R¹ is as defined above,

[0043] which comprises reacting an optically active 2-hydroxycarboxylicacid represented by the above general formula (1) by reaction withthionyl chloride and a basic compound for chlorination with inversion ofthe configuration at 2-position and

[0044] hydrolyzing the thus-obtained optically active 2-chlorocarboxylicacid chloride represented by the-general formula (5).

[0045] Furthermore, the present invention relates to a method ofproducing optically active 2-acetylthiocarboxylic acids represented bythe general formula (3)

[0046] in which R¹ is as defined above,

[0047] which comprises reacting an optically active 2-chlorocarboxylicacid represented by the general formula (2) with a thioacetate salt forsubstitution by acetylthio group with inversion of the configuration at2-position.

[0048] In the following, the present invention is described in detail.

[0049] In the present specification, the following reactions (a) to (c)are included:

[0050] (a) The reaction which converts an optically active2-aminocarboxylic acid of general formula (4) to the correspondingoptically active 2-hydroxycarboxylic acid of general formula (1);

[0051] (b) The reaction which converts the optically active2-hydroxycarboxylic acid (1) to the corresponding optically active2-chlorocarboxylic acid chloride of general formula (5) and the reactionwhich converts the optically active 2-chlorocarboxylic acid chloride (5)to the corresponding optically active 2-chlorocarboxylic acid of generalformula (2); and, further,

[0052] (c) The reaction which converts the optically active2-chlorocarboxylic acid (2) to the corresponding optically active2-acetylthiocarboxylic acid of general formula (3).

[0053] In addition, in the present specification, there is included amethod of crystallizing out an optically active 2-hydroxycarboxylic acidrepresented by the general formula (1).

[0054] In the following, these reactions and method are described indetail one by one.

[0055] 1. Reaction (a)

[0056] In the step of reaction (a) according to the invention, anoptically active 2-hydroxycarboxylic acid (1) is synthesized by reactingan optically active 2-aminocarboxylic acid (4) with a nitrite salt and aprotonic acid.

[0057] In the above general formula (4) or (1), R1 represents asubstituted or unsubstituted alkyl group containing 1 to 12 carbonatoms, a substituted or unsubstituted aryl group containing 6 to 14carbon atoms or a substituted or unsubstituted aralkyl group containing7 to 15 carbon atoms. Specifically, it includes, but is not limited to,methyl, ethyl, isopropyl, tert-butyl, n-octyl, hydroxymethyl, phenyl,p-hydroxyphenyl, benzyl, p-chlorobenzyl, p-fluorobenzyl and naphthylgroup. Substituted or unsubstituted aralkyl groups containing 7 to 15carbon atoms are preferred, and a benzyl group is more preferred.

[0058] As the substituent which the group R1 may have, there may bementioned alkoxy groups containing 1 to 12 carbon atoms, such asmethoxy, ethoxy, t-butyloxy and n-octyloxy group, aryloxy groupscontaining 6 to 14 carbon atoms, such as phenyloxy andp-hydroxyphenyloxy group, aralkyloxy groups containing 7 to 15 carbonatoms, such as benzyloxy, p-chlorobenzyloxy and p-fluorobenzyloxy group,acyl groups containing 1 to 15 carbon atoms, such as acetyl and benzoylgroup, a halogen atom and a hydroxyl group.

[0059] In cases where R¹ is an aryl or aralkyl group, the substituent onthe phenyl group thereof is not particularly restricted but, as such,there may be mentioned, among others, halogen atoms such as fluorine andchlorine atoms, hydroxyl group, alkyl groups containing 1 to 12 carbonatoms, such as methyl and isopropyl group, aralkyl groups containing 7to 15 carbon atoms, such as benzyl group, aryl groups containing 6 to 14carbon atoms, such as phenyl group, alkoxy groups containing 1 to 12carbon atoms, such as methoxy and isopropyloxy group, aralkyloxy groupscontaining 7 to 15 carbon atoms, such as benzyloxy group, aryloxy groupscontaining 6 to 14 carbon atoms, such as phenyloxy group, and acylgroups containing 1 to 15 carbon atoms, such as acetyl and benzoylgroup. Among them, halogen atoms are preferably used. The position ofsuch a substituent is not particularly restricted but the para positionis usual. Although the phenyl group may have a plurality of suchsubstituents as mentioned above, the phenyl group, when substituted,usually has one substituent.

[0060] When the optically active 2-aminocarboxylic acid (4) subjected toreaction (a) according to the invention is in (S) form, the (S) form ofthe optically active 2-hydroxycarboxylic acid (1) is predominant in theproduct obtained. When the optically active 2-aminocarboxylic acid (4)is in (R) form, the (R) form of the optically active 2-hydroxycarboxylicacid (1) is predominant in the product obtained.

[0061] The reaction (a) according to the invention is carried out inaqueous solution. While it is generally suitable to carry out thereaction in water, an organic solvent may coexist in an amount notproducing any adverse effect.

[0062] The nitrite salt to be used in the reaction (a) according to theinvention is not particularly restricted but includes, among others,alkali metal nitrites such as sodium nitrite, potassium nitrite, lithiumnitrite and cesium nitrite. Sodium nitrite is preferred, however. It isparticularly preferred to use the nitrite salt in the form of an aqueoussolution (e.g. 20 to 40% (by weight) aqueous solution of sodiumnitrite).

[0063] As the protonic acid to be used in the reaction (a) according tothe invention, there may be mentioned, among others, inorganic acids,such as sulfuric acid, hydrochloric acid and nitric acid, and organicacids, such as acetic acid and citric acid. Generally, the use ofinorganic acids is expedient and preferred and, for suppressingbyproduct formation and attaining a high reaction yield, sulfuric acidis most preferred among others. The protonic acid can be used in theform of an aqueous solution.

[0064] The reaction (a) according to the invention is carried out byadding the above nitrite salt to an aqueous solution containing anoptically active 2-aminocarboxylic acid (4) and a protonic acid.

[0065] On that occasion, the protonic acid is used in an amount of 1 to3 equivalents, preferably 2 to 3 equivalents, relative to the opticallyactive 2-aminocarboxylic acid (4). The proton concentration (normality)of the aqueous solution containing the optically active2-aminocarboxylic acid (4) and the protonic acid is 0.5 to 2 mol/kg,preferably 1 to 2 mol/kg. When the amount and concentration of theprotonic acid are insufficient, the optical purity of the desiredproduct tends to decrease. When the amount and concentration of theprotonic acid are excessive, the yield tends to decrease.

[0066] The proton concentration (normality) is expressed by thefollowing formula 1:

Proton concentration (normality)=(Number of moles of protonicacid×number of ionic valency)/(amount of water existing in reactionsystem) (mol/kg)

[0067] The number of ionic valency is the absolute value of the ionicvalency of the protonic acid anion. Therefore, according to the aboveformula 1, the proton concentration (normality) of a solution containing98 g (1 mol) of sulfuric acid per kg of water, for instance, is 2mol/kg.

[0068] The nitrite salt is used in an amount of not less than 1 mole,preferably not less than 2 moles, judiciously 2 to 4 moles, per mole ofthe optically active 2-aminocarboxylic acid (4). The addition of thenitrite salt is preferably carried out continuously or in dividedportions. In this case, the addition rate of the nitrite salt per houris 0.2 to 1.5 moles, preferably 0.25 to 1.0 mole, more preferably 0.3 to0.7 moles, per mole of the optically active 2-aminocarboxylic acid (4).Excessively high or low addition rates tend to result in decreasedyields.

[0069] The nitrite salt addition and the subsequent reaction are carriedout at 10 to 80° C., preferably 15 to 60° C., more preferably 20 to 50°C. At excessively low temperatures, the yield tends to decrease and/orthe reaction mixture tends to solidify. At excessively hightemperatures, the yield and optical purity tend to decrease.

[0070] The reactant concentrations depend on the optical active2-aminocaboxylic acid (4) species and other factors, hence cannot bespecified in all cases. As for the amount (weight) of the opticallyactive 2-aminocarboxylic acid (4) used relative to the volume of thereaction mixture at the time of completion of the reaction, forinstance, the lower limit is not less than 1% (w/v), preferably not lessthan 3% (w/v), and the upper limit is not more than 30% (w/v),preferably 20% (w/v). Generally, for example, 3 to 20% (w/v), morepreferably 5 to 15% (w/v), in particular about 8±2% (w/v) is appropriatefor carrying out the reaction.

[0071] The progress of the reaction can be followed by HPLC, forinstance. Generally, the reaction will be complete in 24 hours aftercompletion of the nitrite salt addition.

[0072] After completion of the reaction, the product can be recoveredfrom the reaction mixture by ordinary work-up. For example, the reactionmixture after completion of the reaction is extracted with an ordinaryextracting solvent, such as ethyl acetate, diethyl ether, methylenechloride, toluene or hexane. The desired product can be recovered fromthe thus-obtained extract by distilling off the reaction solvent andextracting solvent by such a procedure as heating under reducedpressure. Although the thus-obtained product is nearly pure, the puritymay further be increased by ordinary purification procedures such aspurification by crystallization, fractional distillation, columnchromatography, etc.

[0073] By using the reaction (a) according to the present invention, itbecomes possible to produce the desired product in very high reactionyield and optical purity.

[0074] 2. Method of Crystallizing Out Optically Active2-hydroxycarboxylic Acids (1)

[0075] In the process of producing the optically active2-hydroxycarboxylic acid (1) by reacting the optically active2-aminocarboxylic acid (4) with a nitrite salt and a protonic acid inaqueous solution, impurities, such as the corresponding α,β-unsaturatedcarboxylic acid (e.g. cinnamic acid, the phenyl group of which may besubstituted) and like related substances as well as the undesiredoptical isomer are formed in many instances in addition to the desired2-hydroxycarboxylic acid (1).

[0076] For removing these impurities and thereby isolating or purifyingthe above optically active 2-hydroxycarboxylic acid (1) expediently andefficiently, the crystallization method according to the invention iscarried out using t-butyl methyl ether and a hydrocarbon solvent. Theuse of t-butyl methyl ether greatly contributes to improvements in yieldand quality.

[0077] The above-mentioned hydrocarbon solvent may be an aliphatichydrocarbon or an aromatic hydrocarbon. The aliphatic hydrocarbon is notparticularly restricted but, for example, linear or cyclic aliphatichydrocarbons containing 5 to 12 carbon atoms can suitably be used. Asspecific examples, there may be mentioned hexane, heptane, octane,decane, cyclohexane, methylcyclohexane, ethylcyclohexane and the like.Among them, hexane, heptane and methylcyclohexane are preferred. Thearomatic hydrocarbon is not particularly restricted but monocyclicaromatic hydrocarbons containing 6 to 12 carbon atoms, for instance, cansuitably be used. Specifically, there may be mentioned benzene, toluene,xylene and ethylbenzene. Among them, toluene is preferred. Form thecrystallization yield viewpoint, aliphatic hydrocarbons are morepreferably used. The hydrocarbon solvent may comprise either one singlespecies or a combination of two or more species.

[0078] As for the quantity ratio between the above-mentioned hydrocarbonsolvent and t-butyl methyl ether, the volume ratio of t-butyl methylether, relative to hydrocarbon solvent, is generally not more than 1,preferably not more than ⅔, still more preferably not more than ½, andgenerally not lower than {fraction (1/30)}, preferably not less than{fraction (1/20)}, still more preferably not less than {fraction(1/10)}. The ratio can appropriately be varied taking into considerationthe solubility and treatment concentration of optically active2-hydroxycarboxylic acid (1), the purification effect (impurity removingeffect) and the physical properties of crystals to be recovered.

[0079] The technique of crystallization to be employed in carrying outthe present invention is not particularly restricted but may comprisecrystallization by cooling, crystallization by concentration,crystallization by solvent replacement (e.g. conversion of the solutioncomprising t-butyl methyl ether to a solution comprising the abovehydrocarbon solvent), crystallization by addition of the abovehydrocarbon solvent to the solution comprising t-butyl methyl ether, orcrystallization by addition of the solution comprising t-butyl methylether to the above hydrocarbon solvent, for instance. Such techniques tobe used in combination are also preferable.

[0080] Preferred among others are the technique comprising effectingcrystallization by adding a hydrocarbon solvent to t-butyl methyl ethersolution containing an optically active 2-hydroxycarboxylic acid (1),and the technique comprising effecting crystallization by adding t-butylmethyl ether solution containing an optically active 2-hydroxycarboxylicacid (1) to a hydrocarbon solvent. In particular, the techniquecomprising adding a hydrocarbon solvent to a t-butyl methyl ethersolution containing an optically active 2-hydroxycarboxylic acid (1) forcrystallization thereof is more preferably used.

[0081] Preferred as the optically active 2-hydroxycarboxylic acid (1)are those in which R¹ is a benzyl group, which may optionally have asubstituent on the aromatic ring. Most preferred among others areoptically active 2-hydroxy-3-phenylpropionic acid and optically active2-hydroxy-3-(p-halophenyl)propionic acids.

[0082] The crystallization according to the present invention isjudiciously carried out using the extract (inclusive of the one afterwashing) obtained, by using t-butyl methyl ether, from an aqueoussolution containing the optically active 2-hydroxycarboxylic acidproduced by the reaction mentioned above, or a concentrate of suchextract.

[0083] The crystallization concentration is not particularly restrictedbut generally is 2 to 30% (w/v), preferably 5 to 20% (w/v), as expressedin terms of weight of optically active 2-hydroxycarboxylic acid (1)relative to volume of solvent.

[0084] The crystallization temperature is not particularly restrictedbut preferably is not lower than 30° C. from the viewpoint of physicalproperties and quality features of crystals to be obtained.

[0085] In carrying out the crystallization, seed crystals may be addedaccording to need.

[0086] The crystal of optically active 2-hydroxycarboxylic acid (1) asformed by the crystallization method of the invention can be recoveredby an ordinary solid-liquid separation technique such as centrifugation,pressure filtration or vacuum filtration. In the step of collectingcrystal, the amount of crystal to be obtained can be maximized bycooling the solution for crystallization finally to a temperature of nothigher than 10° C. The crystal obtained can further be dried accordingto need, for example by reduced pressure (vacuum) drying, to give drycrystals.

[0087] The crystallization method of the invention can also be utilizedas a method of recrystallization or a method of isolation from thereaction mixture.

[0088] By using the crystallization method of the invention, it ispossible to obtain the desired product in very high crystallizationyield and with high quality.

[0089] 3. Reaction (b)

[0090] The reaction (b) according to the invention includes the step ofconverting the optically active 2-hydroxycarboxylic acid represented bythe above general formula (1) to the optically active 2-chlorocarboxylicacid chloride represented by the above general formula (5) by treatmentwith thionyl chloride and a basic compound for chlorination withinversion of the configuration at 2-position, and the step ofconverting, by hydrolysis, the optically active 2-chlorocarboxylic acidchloride (5) to the optically active 2-chlorocarboxylic acid representedby the above general formula (2).

[0091] In the general formula (1), (5) or (2) mentioned above, R¹ is asdefined above. Benzyl is preferred, however.

[0092] In the reaction (b) according to the invention, inversion occursof the configuration at 2-position in general formula (1). Thus, whenthe 2-position in the above general formula (1) has the configuration(S), the configuration at 2-position in the general formulas (5) and (2)is (R) and, when the 2-position in the general formula (1) has theconfiguration (R), the configuration at 2-position in the generalformulas (5) and (2) is (S). The configuration at 2-position in generalformula (1) maybe either (R) or (S). The configuration (S) is preferred,however.

[0093] The rate of inversion of configuration in the invertingchlorination reaction (b) according to the invention should preferablybe not less than 95%. The rate of configurational inversion so referredto herein is expressed in terms of the ratio of the percentage ofenantiomeric excess (% ee) of the product with inversed configuration[2-chlorocarboxylic acid chloride (5) or 2-chlorocarboxylic acid (2)] tothe enantiomeric excess (% ee) of the starting material[2-hydroxycarboxylic acid (1)].

[0094] In the reaction (b) according to the invention, thionyl chlorideis generally used in an amount of not less than 2 moles per mole of theoptically active 2-hydroxycarboxylic acid (1). For suppressing thestarting material or product from being decomposed or racemized andattaining a maximum yield, thionyl chloride is preferably used infurther excess. Therefore, the amount of thionyl chloride to be used inthe reaction (b) according to the invention is generally not less than 2moles and, for maximizing the effects of the present invention, it isnot less than 2.5 moles, preferably not less than 3 moles, per mole ofthe optically active 2-hydroxycarboxylic acid of general formula (1).

[0095] The basic compound to be used in the reaction (b) according tothe invention is not particularly restricted but preferably is anorganic base, an amide group-containing compound or a quaternaryammonium halide.

[0096] The above organic base includes alkylamines, aralkylamines, arylamines and aromatic amines and, specifically, it includes, but is notlimited to, triethylamine, tributylamine, ethyldiisopropylamine,N-methyl-2-pyrrolidine, dimethylaniline, imidazole, pyridine andlutidine. Preferred are triethylamine, diisopropylethylamine andpyridine.

[0097] The above amide group-containing compound specifically includes,but is not limited to, dimethylformamide, dimethylacetamide,tetramethylurea, N-methyl-2-pyrrolidone and hexamethylphosphorictriamide. Preferred are dimethylformamide and N-methyl-2-pyrrolidone.

[0098] The above quaternary ammonium halide specifically includes, butis not limited to, tetramethylammonium chloride, tetraethylammoniumchloride, tetra-n-butylammonium chloride, benzyltrimethylammoniumchloride, benzyltri-n-butylammonium chloride, tetramethylammoniumbromide, tetraethylammonium bromide, tetra-n-butylammonium bromide,benzyltrimethylammonium bromide and benzyltri-n-butylammonium bromide.Preferred is tetra-n-butylammonium chloride.

[0099] Among the basic compounds mentioned above, amide group-containingcompounds are generally preferred. Dimethylformamide,N-methyl-2-pyrrolidone and the like are particularly preferred.

[0100] In the reaction (b) according to the invention, the above basiccompound may be used in a stoichiometric amount or in a larger amountrelative to the optically active 2-hydroxycarboxylic acid of generalformula (1) but, preferably, it is used in an amount not more than 0.5mole per mole of acid (1). Usually, an amount of about 0.1 to 0.5 moleper mole of acid (1) is appropriate to the reaction.

[0101] The reaction solvent to be used in the reaction (b) according tothe invention is preferably an aprotic organic solvent. The aproticorganic solvent is not particularly restricted but includes, amongothers, aliphatic hydrocarbon solvents such as n-hexane andmethylcyclohexane; aromatic hydrocarbon solvents such as benzene,toluene and xylene; ether solvents such as diethyl ether,tetrahydrofuran, 1,4-dioxane, t-butyl methyl ether, dimethoxyethane andethylene glycol dimethyl ether; halogenated hydrocarbon solvents such asmethylene chloride, chloroform and 1,1,1-trichloroethane; andnitrogen-containing solvents such as acetonitrile, dimethylformamide,dimethylacetamide, diethylacetamide, dimethylbutyramide,N-methyl-2-pyrrolidone and hexamethylphosphoric triamide. These maybeused singly or two or more of them may be used in combination.

[0102] Particularly when an ether solvent such as diethyl ether,tetrahydrofuran, 1,4-dioxane, t-butyl methyl ether, dimethoxyethane orethylene glycol dimethyl ether or an aromatic hydrocarbon solvent suchas benzene, toluene or xylene is used, the reaction can proceed withhigh configurational inversion rate and high yield to give the opticallyactive 2-chlorocarboxylic acid chloride (5) of high purity from theoptically active 2-hydroxycarboxylic acid (1). Tetrahydrofuran,dimethoxyethane, 1, 4-dioxane and toluene are preferred among others,and tetrahydrofuran and toluene are particularly preferred.

[0103] The reaction temperature is preferably −20° C. to 120° C., morepreferably 0° C. to 80° C., most preferably 20° C. to 60° C.

[0104] The reaction concentration is not particularly restricted but isnot less than 5% (w/v), preferably not less than 10% (W/v), as expressedin terms of the amount of the optically active 2-hydroxycarboxylic acidof general formula (1) relative to the amount of the solvent.

[0105] The procedure for carrying out the reaction (b) according to theinvention is not particularly restricted. For example, thionyl chlorideis added to a solution of the optically active 2-hydoxycarboxylic acid(1), and the mixture is stirred for several hours. Thereafter, theabove-mentioned basic compound is added and, then, the resulting mixtureis stirred for several hours, whereby the optically active2-chlorocarboxylic acid chloride (5) can be obtained. The opticallyactive 2-chlorocarboxylic acid chloride (5) can be isolated, forexample, by evaporating the solvent from the reaction mixture and thendistilling the concentrate under reduced pressure.

[0106] Further, the optically active 2-chlorocarboxylic acid chloride(5) can be converted to the optically active 2-chlorocarboxylic acid (2)by hydrolysis.

[0107] Generally, the above hydrolysis reaction can be carried out byadding water at room temperature or at lower temperature to the reactionmixture containing, or a solution of, the optically active2-chlorocarboxylic acid chloride (5) and stirring the mixture forseveral minutes to several hours.

[0108] The product can be recovered from this reaction mixture byordinary work-up procedure. For example, the reaction mixture aftercompletion of the hydrolysis reaction is extracted with an ordinaryextracting solvent, such as ethyl acetate, diethyl ether, methylenechloride, toluene or hexane. The reaction solvent and extracting solventare distilled off from the extract obtained by such a procedure asheating under reduced pressure, whereby the optically active2-chlorocarboxylic acid (2) can be obtained.

[0109] It is also possible to once isolate the optically active2-chlorocarboxylic acid chloride (5) by such a procedure asconcentration or distillation without hydrolysis and then subjecting thechloride (5) to the hydrolysis reaction and subsequent procedure.

[0110] Furthermore, in extracting the optically active2-chlorocarboxylic acid (2), a procedure may also be performed at leastonce which comprises distributing the optically active2-chlorocarboxylic acid (2) in an aqueous phase under neutral to basicconditions to thereby remove impurities into an organic solvent.Moreover, a procedure may be performed which comprises distributing theoptically active 2-chlorocarboxylic acid (2) into an organic solventfinally under acidic conditions to thereby remove impurities, inclusiveof salts resulting from neutralization, into an aqueous phase. Althoughthe thus-obtained product is nearly pure, the product can further bepurified by an ordinary technique, such as purification bycrystallization, fractional distillation or column chromatography, tofurther increase the purity.

[0111] 4. Reaction (c)

[0112] In the step of reaction (c) according to the invention, theoptically active 2-chlorocarboxylic acid represented by the abovegeneral formula (2) is reacted with a thioacetate salt for substitutionby acetylthio group with inversion of the configuration at 2-position.Thus is prepared the corresponding optically active2-acetylthiocarboxylic acid represented by the general formula (3).

[0113] In the general formula (2) or (3) mentioned above, R¹ is asdefined hereinabove. Preferred is a benzyl group.

[0114] In the reaction (c) according to the invention, the configurationat 2-position in the general formula (2) is inverted. Namely, when the2-position configuration in the above general formula (2) is (S), the2-position configuration in general formula (3) is (R) and, when the2-position configuration in general formula (2) is (R), the 2-positionconfiguration in general formula (3) is (S). The 2-positionconfiguration in general formula (2) may be either of (R) and (S) butpreferably is (R).

[0115] In the reaction (c) according to the invention, the rate ofconfigurational inversion is preferably not less than 95%. The rate ofconfigurational inversion so referred to herein is expressed in terms ofthe ratio of the percentage of enantiomeric excess (% ee) of the productwith inversed configuration [2-acetylthiocarboxylic acid (3)] to theenantiomeric excess (% ee) of the starting material [2-chlorocarboxylicacid (2)].

[0116] In the reaction (c) according to the invention, the thioacetatesalt is not particularly restricted but includes salts of thioaceticacid with bases, preferably alkali metal thioacetates such as sodiumthioacetate, potassium thioacetate, lithium thioacetate and cesiumthioacetate. Among them, potassium thioacetate is preferably used.

[0117] Alternatively, the reaction may be carried out using thioaceticacid and a base (e.g. the hydroxide, hydride or alkoxide of an alkalimetal) so as to prepare the corresponding thioacetate salt in thereaction system. The alkali metal hydroxide mentioned above includes,but is not limited to, lithium hydroxide, sodium hydroxide and potassiumhydroxide. Among them, potassium hydroxide is preferred. The alkalimetal hydride mentioned above includes, but is not limited to, lithiumhydride, sodium hydride and potassium hydride. Among them, potassiumhydride is preferred. The alkali metal alkoxide mentioned aboveincludes, but is not limited to, lithium methoxide, sodium methoxide andpotassium methoxide. Potassium methoxide is preferred, however.

[0118] In the reaction (c) according to the invention, the thioacetatesalt is used in an amount of 1 to 5 equivalents, preferably 1 to 2equivalents, relative to the optically active 2-chlorocarboxylic acid ofgeneral formula (2).

[0119] The reaction (c) according to the invention is preferably carriedout in the presence of an aprotic polar solvent. The aprotic polarsolvent is not particularly restricted but includes, among others,water-soluble ether compounds such as tetrahydrofuran, 1,4-dioxane,dimethoxyethane and ethylene glycol dimethyl ether; ester compounds suchas ethyl acetate and butyl acetate; ketone compounds such as acetone andmethyl ethyl ketone; halogenated compounds such as methylene chloride,chloroform and 1,1,1-trichloroethane; sulfur-containing compounds suchas dimethyl sulfoxide; and nitrogen-containing compounds such asacetonitrile, dimethylformamide, dimethylacetamide, diethylacetamide,dimethylbutyramide, N-methyl-2-pyrrolidone and hexamethylphosphorictriamide. These may be used singly or two or more of them may be used incombination. Among them, water-soluble ether compounds, ester compounds,ketone compounds, sulfur-containing compounds and nitrogen-containingcompounds are preferably used. More specifically, aprotic polarcompounds having a dielectric constant of not less than 15 and a dipolemoment of not less than 2.5 D are preferred. Suited for use among themare those nitrogen-containing compounds mentioned above which areliquid. From the viewpoint of reaction yield and rate of configurationalinversion, amide group-containing liquid compounds are particularlypreferred and, specifically, dimethylformamide, dimethylacetamide,diethylacetamide, dimethylbutyramide and N-methyl-2-pyrrolidone arepreferred.

[0120] For causing such aprotic polar compounds to exist in the reactionsystem, one of such compounds which exists as a liquid may be used asthe reaction solvent in the step of thioacetylation or one of suchcompounds which is a solid may be used in the form of a solution inwater and/or another solvent such as mentioned below. Among thealternatives, the use as the reaction solvent is expedient. In caseswhere an aprotic polar solvent is used as the reaction solvent, thereaction solvent may comprise the aprotic polar compound alone or amixed solvent composed of it and water and/or another organic solvent tobe mentioned below.

[0121] The reaction solvent to be used in carrying out the reaction (c)according to the invention is generally water, an organic solvent or amixture thereof. While the organic solvent includes the above-mentionedaprotic polar compounds, the other organic solvents are not particularlyrestricted but include, among others, alcohol solvents such as methanol,ethanol, butanol, isopropanol, ethylene glycol and methoxyalcohol;hydrocarbon solvents such as benzene, toluene, n-hexane and cyclohexane;and water-insoluble ether solvents such as diethyl ether, diisopropylether, dibutyl ether and t-butyl methyl ether. These may be used singlyor two or more of them may be used in combination.

[0122] When the reaction yield is low with the solvent employed, a phasetransfer catalyst may be used for improving the yield. The phasetransfer catalyst to be used is not particularly restricted butincludes, among others, crown ethers such as12-crown-4,15-crown-5,18-crown-6,24-crown-8, dibenzo-18-crown-6,dibenzo-24-crown-8, dicyclohexyl-18-crown-6 and dicyclohexyl-24-crown-8;cryptands such as cryptand[2,2], cryptand[2,1,1], cryptand[2,2,1],cryptand[2,2,2] and cryptand[2B,2,2]; and quaternary ammonium salts suchas trioctylmethylammonium chloride (trade name: ALIQUAT 336),trioctylmethylammonium bromide and methyltrialkyl (C₈ to C₁₀) ammoniumchloride (trade name: Adogen 464). Among the phase transfer catalystsmentioned above, quaternary ammonium salts are generally preferred and,among them, trioctylmethylammonium chloride is judiciously used.

[0123] The level of addition of the phase transfer catalyst is notparticularly restricted but, in general, it is preferably 0.05 to 5 molepercent, more preferably 0.3 to 1 mole percent, relative to theoptically active 2-chlorocarboxylic acid of general formula (2).

[0124] The reaction temperature is preferably −20° C. to 120° C., morepreferably 0° C. to 50° C.

[0125] After completion of the reaction, the product can be recoveredfrom the reaction mixture by ordinary work-up. For example, water isadded to the reaction mixture after completion of the reaction and anextraction procedure is performed using an ordinary extracting solventsuch as ethyl acetate, diethyl ether, methylene chloride, toluene orhexane. The reaction solvent and extracting solvent are distilled off,for example by heating under reduced pressure, whereby the product canbe recovered. It is also possible to distill off the reaction solvent byheating under pressure, for instance, directly after completion of thereaction and then perform the same procedure as mentioned above.Although the thus-obtained product is nearly pure, the purity can befurther increased by an ordinary purification procedure such aspurification by crystallization, fractional distillation or columnchromatography.

BEST MODES FOR CARRYING OUT THE INVENTION

[0126] The following examples illustrate the present invention infurther detail. These examples are, however, by no means limitative ofthe scope of the present invention.

[0127] In the following, the assay of 2-hydroxy-3-phenylpropionic acidand the measurement of the apparent purity of2-hydroxy-3-(p-fluorophenyl) propionic acid were carried out using thefollowing analytical system. [Column: Develosil ODS-HG-3 (product ofNomura Chemical), 150 mm×4.6 mm I.D., mobile phase: 0.1% (wt/v)phosphoric acid water/acetonitrile=75/25, flow rate: 1.0 ml/min,detection: UV 210 nm, column temperature: 40° C., retention time:2-hydroxy-3-phenylpropionic acid 3.9 min,2-hydroxy-3-(p-fluorophenyl)propionic acid 5.1 min].

[0128] The above-mentioned apparent purity is expressed by the formula2:

Apparent purity=(integrated area value for2-hydroxy-3-(p-fluorophenyl)propionic acid/total integrated area valuefor all compounds detected)×100 (%)

[0129] The optical purity evaluation of 2-hydroxy-3-phenylpropionic acidand. 2-hydroxy-3-(p-fluorophenyl)propionic acid was made byderivatization into the corresponding methyl ester respectively by themethod mentioned below. Optical purity evaluation of2-hydroxy-3-phenylpropionic acid The product (20 mg, 0.12 mmol) wasdissolved in a mixed solvent composed of 1 ml of methanol and 3.5 ml oftoluene, 166 mg (0.15 mmol) of a 10% solution oftrimethylsilyldiazomethane was added dropwise, the reaction was allowedto proceed at room temperature for 30 minutes, the solvent was thendistilled off under reduced pressure, and the concentrate was purifiedon a silica gel (hexane/ethyl acetate=4/1) to give methyl2-hydroxy-3-phenylpropionate. This methyl ester was analyzed by HPLC[column: Chiralcel OD-H (product of Daicel Chemical Industries), mobilephase: hexane/isopropanol=98/2, flow rate: 1.0 ml/min, detection: UV 210nm, column temperature: 5° C., retention time: S form 32 min, R form 30min].

[0130] Optical Purity Evaluation of2-hydroxy-3-(p-fluorophenyl)propionic Acid

[0131] The product (20 mg, 0.11 mmol) was dissolved in a mixed solventcomposed of 1 ml of methanol and 3.5 ml of toluene, 166 mg (0.15 mmol)of a 10% solution of trimethylsilyldiazomethane was added dropwise, thereaction was allowed to proceed at room temperature for 30 minutes, thesolvent was then distilled off under reduced pressure, and theconcentrate was purified on a silica gel (hexane/ethyl acetate=4/1) togive methyl 2-hydroxy-3-(p-fluorophenyl)propionate. This methyl esterwas analyzed by HPLC [column: Chiralcel OJ (product of Daicel ChemicalIndustries), mobile phase: hexane/ethanol=95/5, flow rate: 1.0 ml/min,detection: UV 210 nm, column temperature: 20° C., retention time: R form15 min, S form 16 min].

EXAMPLE 1 Production of (2S)-2-hydroxy-3-phenylpropionic Acid

[0132]

[0133] L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution of8.88 g (90.5 mmol) of concentrated sulfuric acid in 110 g of water andthen, at an inside temperature of 20° C., a mixture of 10.45 g (151.5mmol) of sodium nitrite and 20 g of water was added over 5 hours. Afteraddition, the mixture was stirred at 20° C. for 20 hours, 100 ml oft-butyl methyl ether was then added and, after 30 minutes of stirring at20° C., the organic phase was separated (extract 1). Further, 50 ml oft-butyl methyl ether was added to the aqueous phase, the mixture wasstirred at 20° C. for 30 minutes, and the organic phase was separated(extract 2). The extracts 1 and 2 were combined. The combined extract(116.5 g) contained 8.6 g of (2S)-2-hydroxy-3-phenylpropionic acid(yield 86%, optical purity 95.9% ee). The proton concentration(normality) in the reaction of this example was 1.7 mol/kg, the amountof the protonic acid was 3.0 equivalents (relative to L-phenylalanine),and the reaction temperature was 20° C.

EXAMPLE 2 Production of (2S)-2-hydroxy-3-phenylpropionic Acid

[0134] L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution of5.93 g (60.5 mmol) of concentrated sulfuric acid in 110 g of water andthen, at an inside temperature of 20° C., a mixture of 10.45 g (151.5mmol) of sodium nitrite and 20 g of water was added over 5 hours. Afteraddition, the mixture was further stirred at 20° C. for 20 hours and,thereafter, the same work-up procedure as in Example 1 was followed. Thecombined extract (116.1 g) obtained contained 8.7 g of(2S)-2-hydroxy-3-phenylpropionic acid (yield 87%, optical purity 95.2%ee). The proton concentration (normality) in the reaction of thisexample was 1.1 mol/kg, the amount of the protonic acid was 2.0equivalents (relative to L-phenylalanine), and the reaction temperaturewas 20° C.

EXAMPLE 3 Production of (2S)-2-hydroxy-3-phenylpropionic Acid

[0135] L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution of4.15 g (42.4 mmol) of concentrated sulfuric acid in 110 g of water andthen, at an inside temperature of 20° C., a mixture of 10.45 g (151.5mmol) of sodium nitrite and 20 g of water was added over 5 hours. Afteraddition, the mixture was further stirred at 20° C. for 20 hours and,thereafter, the same work-up procedure as in Example 1 was followed. Thecombined extract (115.8 g) obtained contained 8.7 g of(2S)-2-hydroxy-3-phenylpropionic acid (yield 87%, optical purity 92.0%ee). The proton concentration (normality) in the reaction of thisexample was 0.8 mol/kg, the amount of the protonic acid was 1.4equivalents (relative to L-phenylalanine), and the reaction temperaturewas 20° C.

COMPARATIVE EXAMPLE 1

[0136] L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution of14.83 g (151.3 mmol) of concentrated sulfuric acid in 110 g of water andthen, at an inside temperature of 20° C., a mixture of 10.45 g (151.5mmol) of sodium nitrite and 20 g of water was added over 5 hours. Afteraddition, the mixture was further stirred at 20° C. for 20 hours and,thereafter, the same work-up procedure as in Example 1 was followed. Thecombined extract (114.4 g) obtained contained 6.9 g of(2S)-2-hydroxy-3-phenylpropionic acid (yield 69%, optical purity 96.5%ee). The proton concentration (normality) in the reaction of thiscomparative example was 2.7 mol/kg, the amount of the protonic acid was5.0 equivalents (relative to L-phenylalanine), and the reactiontemperature was 20° C.

COMPARATIVE EXAMPLE 2

[0137] L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution of8.88 g (90.5 mmol) of concentrated sulfuric acid in 110 g of water andthen, at an inside temperature of 0° C., a mixture of 10.45 g (151.5mmol) of sodium nitrite and 20 g of water was added over 5 hours. Afteraddition, the mixture was further stirred at 0° C. for 20 hours and,thereafter, the same work-up procedure as in Example 1 was followed. Thecombined extract (113.7 g) obtained contained 7.0 g of(2S)-2-hydroxy-3-phenylpropionic acid (yield 70%, optical purity 96.6%ee). The proton concentration (normality) in the reaction of thisexample was 1.7 mol/kg, the amount of the protonic acid was 3.0equivalents (relative to L-phenylalanine) and the reaction temperaturewas 0° C.

COMPARATIVE EXAMPLE 3

[0138] A solution of 14 g (217 mmol) of sodium nitrite in 20 ml of waterwas added dropwise to a solution of 14 g (85 mmol) of L-phenylalanine in100 ml of 1 N sulfuric acid at 0° C. over 3 hours, and the mixture wasstirred overnight at room temperature. After extraction with three100-ml portions of ethyl acetate, the organic phase was dried oversodium sulfate. The optical purity of (2S)-2-hydroxy-3-phenylpropionicacid in this extract was 93.0% ee. The solvent was distilled off underreduced pressure to give 12 g of crude (2S)-2-hydroxy-3-phenylpropionicacid. Further, this crude product was purified by recrystallizationusing 35 ml of ethyl acetate to give 7.5 g (yield 53%) of the desired(2S)-2-hydroxy-3-phenylpropionic acid. The proton concentration(normality) in the reaction of this comparative example was 1.0 mol/kg,the amount of the protonic acid was 1.2 equivalents (relative toL-phenylalanine), and the reaction temperature was 0° C. to roomtemperature.

[0139]¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.34-7.25 (5H, m), 4.51 (1H, dd,J=7.3 Hz, 4.4 Hz), 3.21 (1H, dd, J=14.2 Hz, 4.4 Hz), 3.00 (1H, dd,J=13.7 Hz, 7.4 Hz).

EXAMPLE 4 Production of (2S)-2-hydroxy-3-phenylpropionic Acid

[0140] L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution of8.88 g (90.5 mmol) of concentrated sulfuric acid in 110 g of water andthen, at an inside temperature of 40° C., a mixture of 10.45 g (151.5mmol) of sodium nitrite and 20 g of water was added over 5 hours. Afteraddition, the mixture was further stirred at 40° C. and, thereafter, thesame work-up procedure as in Example 1 was followed. The combinedextract (146.9 g) obtained contained 8.9 g of(2S)-2-hydroxy-3-phenylpropionic acid (yield 89%, optical purity 94.3%ee). The proton concentration (normality) in the reaction of thisexample was 1.7 mol/kg, the amount of the protonic acid was 3.0equivalents (relative to L-phenylalanine), and the reaction temperaturewas 40° C.

EXAMPLE 5 Production of (2S)-2-hydroxy-3-phenylpropionic Acid

[0141] L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution of8.88 g (90.5 mmol) of concentrated sulfuric acid in 110 g of water andthen, at an inside temperature of 70° C., a mixture of 10.45 g (151.5mmol) of sodium nitrite and 20 g of water was added over 5 hours. Afteraddition, the mixture was further stirred at 70° C. for 20 hours and,thereafter, the same work-up procedure as in Example 1 was followed. Thecombined extract (147.3 g) obtained contained 8.5 g of(2S)-2-hydroxy-3-phenylpropionic acid (yield 85%, optical purity 92.0%ee). The proton concentration (normality) in the reaction of thisexample was 1.7 mol/kg. The amount of the protonic acid was 3.0equivalents (relative to L-phenylalanine) and the reaction temperaturewas 70° C.

EXAMPLE 6 Production of (2S)-2-hydroxy-3-phenylpropionic Acid

[0142] L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution of8.88 g (90.5 mmol) of concentrated sulfuric acid in 110 g of water andthen, at an inside temperature of 20° C., a mixture of 10.45 g (151.5mmol) of sodium nitrite and 20 g of water was added over 2 hours. Afteraddition, the mixture was stirred at 20° C. for 20 hours and,thereafter, the same work-up procedure as in Example 1 was followed. Thecombined extract (116.3 g) obtained contained 8.5 g of(2S)-2-hydroxy-3-phenylpropionic acid (yield 85%, optical purity 94.0%ee). The proton concentration (normality) in the reaction of thisexample was 1.7 mol/kg. The amount of the protonic acid was 3.0equivalents (relative to L-phenylalanine) and the reaction temperaturewas 20° C.

COMPARATIVE EXAMPLE 4

[0143] L-Phenylalanine (10.00 g, 60.5 mmol) was added to a dilution of8.88 g (90.5 mmol) of concentrated sulfuric acid in 55 g of water andthen, at an inside temperature of 20° C., a mixture of 10.45 g (151.5mmol) of sodium nitrite and 20 g of water was added over 5 hours. Afteraddition, the mixture was further stirred at 20° C. for 20 hours and,thereafter, the same work-up procedure as in Example 1 was followed. Thecombined extract (116.5 g) obtained contained 6.4 g of(2S)-2-hydroxy-3-phenylpropionic acid (yield 64%, optical purity 96.6%ee). The proton concentration (normality) in the reaction of thisexample was 3.3 mol/kg, the amount of the protonic acid was 3.0equivalents (relative to L-phenylalanine), and the reaction temperaturewas 20° C.

COMPARATIVE EXAMPLE 5

[0144] This comparative example was to confirm the reaction results ofthe method described in J. Amer. Chem. Soc., 86, 5326-5330, 1964.

[0145] L-Phenylalanine hydrochloride (12.2 g, 60.5 mmol) was added to183 ml of 5% sulfuric acid (sulfuric acid: 96.0 mmol) and the solutionwas treated with a mixture of 8.35 g (121 mmol) of sodium nitrite and44.5 g of water at 0° C. for 3 hours. Thereafter, 100 ml of diethylether was added to the reaction mixture and, after stirring, the organicphase was separated (extract 1). Further, 50 ml of diethyl ether wasadded to the aqueous phase and, after stirring, the organic phase wasseparated (extract 2). The extracts 1 and 2 were combined. The combinedextract (95.0 g) contained 4.2 g of (2S)-2-hydroxy-3-phenylpropionicacid (yield 42%, optical purity 92.6% ee). The proton concentration(normality) in the reaction of this comparative example was 1.4 mol/kg,the amount of the protonic acid was 4.0 equivalents (relative toL-phenylalanine), and the reaction temperature was 0° C.

COMPARATIVE EXAMPLE 6

[0146] This comparative example was to confirm the reaction results ofthe method described in J. Heterocyclic Chem., 29, 431-438, 1992.

[0147] Crystalline sodium nitrite (16.6 g, 241 mmol) was added to amixture of 120 ml of 1 M sulfuric acid (sulfuric acid: 120 mmol) and10.0 g (60.5 mmol) of L-phenylalanine at 0° C. over 5 hours. Afteraddition, the temperature was raised to room temperature (15° C.), andthe mixture was stirred overnight. Ethyl acetate (40 ml) was added tothis reaction mixture and, after stirring, the organic phase wasseparated. The above procedure was further repeated twice. The organicphases were combined. The total extract (115.2 g) contained 6.6 g of(2S)-2-hydroxy-3-phenylpropionic acid (yield 66%, optical purity 96.2%ee). The proton concentration (normality) in the reaction of thiscomparative example was 2.1 mol/kg, the amount of the protonic acid was4.0 equivalents (relative to L-phenylalanine), and the reactiontemperature was 0° C. during the addition of sodium nitrite and roomtemperature (15° C.) after completion of the addition.

EXAMPLE 7 Crystallization of (2S)-2-hydroxy-3-phenylpropionic Acid

[0148] A portion of the (2S)-2-hydroxy-3-phenylpropionic acid/t-butylmethyl ether extract obtained in Example 2 (66.7 g, containing 5.0 g of(2S)-2-hydroxy-3-phenylpropionic acid, optical purity 95.2% ee) wasconcentrated under reduced pressure to give 20.0 g of a concentrate.While stirring this concentrate, 60 ml of hexane was gradually added at40° C. to thereby cause precipitation of crystals. Then, the resultingmixture was cooled to 5° C. and further stirred for 2 hours. Thecrystals formed were filtered off under reduced pressure and then washedwith two 10-ml portions of hexane/t-butyl methyl ether (75/25 byvolume). The wet crystals obtained were dried under reduced pressure(vacuum) (full vacuum, 40° C., overnight) to give 4.5 g of(2S)-2-hydroxy-3-phenylpropionic acid (purity 98.7%, optical purity notlower than 99.9% ee, crystallization yield 89%).

EXAMPLE 8 Crystallization of (2S)-2-hydroxy-3-phenylpropionic Acid

[0149] A (2S)-2-hydroxy-3-phenylpropionic acid/t-butyl methyl etherextract separately obtained (3,450 g, containing 253.3 g of(2S)-2-hydroxy-3-phenylpropionic acid, optical purity 93.0% ee) wasconcentrated under reduced pressure to give 734 g of a concentrate.While stirring this concentrate, 2,230 ml of hexane was added over 3hours at 40° C. to thereby cause precipitation of crystals. Then, theresulting mixture was cooled to 5° C. and further stirred for 2 hours.The crystals formed were filtered off under reduced pressure and thenwashed with two 250-ml portions of hexane/t-butyl methyl ether (75/25 byvolume). The wet crystals obtained were dried under reduced pressure(vacuum) (full vacuum, 40° C., overnight) to give 232.2 g of(2S)-2-hydroxy-3-phenylpropionic acid (purity 98.2%, optical purity99.8% ee, crystallization yield 90%).

COMPARATIVE EXAMPLE 7

[0150] A (2S)-2-hydroxy-3-phenylpropionic acid/ethyl acetate extractseparately obtained (83.3 g, containing 5.0 g of(2S)-2-hydroxy-3-phenylpropionic acid, optical purity 93.7% ee) wasconcentrated under reduced pressure to give 20.0 g of a concentrate.While stirring this concentrate, 50 ml of hexane was gradually added at40° C. to thereby cause precipitation of crystals. Then, the resultingmixture was cooled to 5° C. and further stirred for 2 hours. Thecrystals formed were filtered off under reduced pressure and then washedwith two 10-ml portions of hexane/ethyl acetate (75/25 by volume). Thewet crystals obtained were dried under reduced pressure (vacuum) (fullvacuum, 40° C., overnight) to give 4.5 g of(2S)-2-hydroxy-3-phenylpropionic acid (purity 98.8%, optical purity98.0% ee, crystallization yield 88%).

EXAMPLE 9 Crystallization of (2S)-2-hydroxy-3-phenylpropionic Acid

[0151] A (2S)-2-hydroxy-3-phenylpropionic acid/t-butyl methyl etherextract separately obtained (66.4 g, containing 5.0 g of(2S)-2-hydroxy-3-phenylpropionic acid, optical purity 95.3% ee) wasconcentrated under reduced pressure to give 16.7 g of a concentrate.While stirring this concentrate, 150 ml of toluene was gradually addedat 40° C. to thereby cause precipitation of crystals. Then, theresulting mixture was cooled to 5° C. and further stirred for 2 hours.The crystals formed were filtered off under reduced pressure and thenwashed with two 10-ml portions of toluene/t-butyl methyl ether (90/10 byvolume). The wet crystals obtained were dried under reduced pressure(vacuum) (full vacuum, 40° C., overnight) to give 4.0 g of(2S)-2-hydroxy-3-phenylpropionic acid (purity 99.2%, optical purity notlower than 99.9% ee, crystallization yield 80%).

EXAMPLE 10 Crystallization of (2R)-2-hydroxy-3-(p-fluorophenyl)propionicAcid

[0152] A mixture of 4.96 g of crude crystals of(2R)-2-hydroxy-3-(p-fluorophenyl)propionic acid (apparent purity 80%,optical purity 97.2% ee) and 10 ml of t-butyl methyl ether was slowlyadded to 40 ml of hexane containing 20 mg of seed crystals added, withstirring at 30° C. to thereby cause precipitation of crystals, and themixture was then cooled to 5° C. and further stirred for 2 hours. Thecrystals formed were filtered off under reduced pressure and then washedwith two 10-ml portions of hexane/t-butyl methyl ether (80/20 by volume)The wet crystals obtained were dried under reduced pressure (vacuum)(full vacuum, 40° C., overnight) to give 3.80 g of(R)-2-hydroxy-3-(p-fluorophenyl)propionic acid (apparent purity 99%,optical purity 99.9% ee, crystallization yield 95%).

EXAMPLE 11 (2R)-2-Chloro-3-phenylpropionic Acid Chloride

[0153]

[0154] Toluene (50 ml) was added to 5.0 g (30.1 mmol) of(2S)-2-hydroxy-3-phenylpropionic acid, 10.7 g (90.3 mmol) of thionylchloride was added dropwise, and the mixture was stirred at 40° C. for 2hours. To the mixture was added 0.44 g (6.0 mmol) of dimethylformamide,and the resulting mixture was stirred at 40° C. for 24 hours. Thereaction mixture was concentrated under reduced pressure, 90 ml oftoluene was further added to the concentrate, and the dilution was againconcentrated under reduced pressure. The thus-obtained concentrate wasdistilled under reduced pressure (boiling point: about 1 mmHg, 102-103°C.) to give 3.1 g (14.1 mmol, yield 47%) of(2R)-2-chloro-3-phenylpropionic acid chloride.

[0155]¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.36-7.23 (5H, m), 4.71 (1H, t,J=7.3 Hz), 3.47 (1H, dd, J=14.2 Hz, 6.4 Hz), 3.02 (1H, dd, J=14.2 Hz,7.8 Hz). ¹³C NMR (100 MHz. CDCl₃) δ (ppm): 170.25, 134.30, 129.36,128.83, 127.84, 65.44, 40.68. IR (neat) (cm⁻¹): 3034, 1783, 1605, 1499,1456, 1435, 1246, 1175, 1080, 1003, 925, 887, 835, 737, 698, 648, 548,484.

EXAMPLE 12 (2R)-2-Chloro-3-phenylpropionic Acid

[0156]

[0157] Thionyl chloride (0.66 ml, 9.0 mmol) was added dropwise to asolution of (2S)-2-hydroxy-3-phenylpropionic acid (500 mg, 3.0 mmol,optical purity 100% ee (S)) in 5 ml of tetrahydrofuran at roomtemperature, and the mixture was stirred for 15 hours. To the reactionmixture was added 170 mg (0.60 mmol) of tetra-n-butylammonium chloride,and the mixture was heated at 40° C. for 4 hours. Water (5 ml) was addedto the reaction mixture and, after 30 minutes of stirring, the mixturewas extracted with 90 ml of ethyl acetate. The organic phase was washedwith 10 ml of a saturated aqueous solution of sodium chloride and thendried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure to give 499 mg (yield 90%) of the desired(2R)-chloro-3-phenylpropionic acid.

[0158]¹H NMR (400 MHz. CDCl₃) δ (ppm): 7.36-7.23 (5H, m), 4.49 (1H, t,J=7.3 Hz), 3.39 (1H, dd, J=14.1 Hz, 6.9 Hz), 3.02 (1H, dd, J=14.2 Hz,7.8 Hz).

[0159] The optical purity of the product was determined byderivatization into the corresponding methyl ester by the followingmethod. The product (25 mg, 0.14 mmol) was dissolved in a mixed solventcomposed of 1 ml of methanol and 3.5 ml of toluene, 200 mg (0.18 mmol)of a 10% solution of trimethylsilyldiazomethane in hexane was addeddropwise at room temperature and, after allowing the reaction to proceedat room temperature for 30 minutes, the solvents were distilled offunder reduced pressure. The concentrate was purified on a silica gelcolumn (hexane/ethyl acetate=4:1) to give methyl2-chloro-3-phenylpropionate. This methyl ester was analyzed by HPLC[column: Chiralcel OD-H (product of Daicel Chemical Industries), eluent:hexane/isopropanol=100:1, flow rate: 1.0 ml/min, temperature: 40° C.,detection wavelength: 210 nm, retention time: R form 26 min, S form 28min] and found to have an optical purity of 98.9% ee (R) (rate ofconfigurational inversion 98.9%).

EXAMPLE 13 (2R)-2-Chloro-3-phenylpropionic Acid

[0160] Thionyl chloride (43.8 g, 368.4 mmol) was added dropwise to asolution of 20.4 g (122.8 mmol) of (2S)-2-hydroxy-3-phenylpropionic acid(optical purity 100% ee (S)) in 200 ml of tetrahydrofuran, and themixture was stirred at 35 to 40° C. for 2 hours. To that solution wasadded 1.8 g (24.6 mmol) of dimethylformamide, and the mixture wasstirred at 42 to 44° C. for 6 hours. This reaction mixture was cooledand, while maintaining the temperature at 20° C., 70 ml of water wasadded dropwise and, after about an hour of stirring, the mixture wasextracted with 200 ml of toluene. Water (70 ml) was added to the organicphase and, after pH adjustment to 9.0 with a 30% aqueous solution ofsodium hydroxide, the organic phase was removed by phase separation. Tothe aqueous phase obtained was added 200 ml of toluene, the pH wasadjusted to 1.0 with 35% aqueous hydrochloric acid, and the aqueousphase was removed by phase separation. The toluene was distilled offunder reduced pressure from the thus-obtained toluene phase to give 21.1g (114.3 mmol, yield 93%) of (2R)-2-chloro-3-phenylpropionic acid. Theoptical purity of the product as determined by the same method as inExample 12 was 99.8% ee (R) (rate of configurational inversion 99.8%).

EXAMPLE 14 (2R)-2-Chloro-3-phenylpropionic Acid

[0161] 1,4-Dioxane (200 ml) was added to 20.4 g (122.8 mmol) of(2S)-2-hydroxy-3-phenylpropionic acid (optical purity 100% ee (S)), 43.8g (368.4 mmol) of thionyl chloride was added dropwise, and the mixturewas stirred at 40° C. for 2 hours. To that solution was added 1.8 g(24.6 mmol) of dimethylformamide, and the mixture was stirred at 40° C.for 6 hours. This reaction mixture was cooled and, while maintaining thetemperature at 20° C., 70 ml of water was added dropwise and, afterabout an hour of stirring, the mixture was extracted with 200 ml oftoluene. Water (70 ml) was added to the organic phase and, after pHadjustment to 9.0 with a 30% aqueous solution of sodium hydroxide, theorganic phase was removed by phase separation. To the aqueous phaseobtained was added 200 ml of toluene, the pH was adjusted to 1.0 with35% aqueous hydrochloric acid, and the aqueous phase was removed byphase separation. The toluene was distilled off under reduced pressurefrom the thus-obtained toluene phase to give 19.1 g (103.3 mmol, yield84%) of (2R)-2-chloro-3-phenylpropionic acid. The optical purity of theproduct as determined by the same method as in Example 12 was 99.7% ee(R) (rate of configurational inversion 99.7%).

EXAMPLE 15 (2R)-2-Chloro-3-phenylpropionic Acid

[0162] Thionyl chloride (43.8 g, 368.4 mmol) was added dropwise to asolution of 20.4 g (122.8 mmol) of (2S)-2-hydroxy-3-phenylpropionic acid(optical purity 100% ee (S)) in 200 ml of toluene, and the mixture wasstirred at 40° C. for 2 hours. To that solution was added 1.8 g (24.6mmol) of dimethylformamide, and the mixture was stirred at 40° C. for 24hours. This reaction mixture was cooled and, while maintaining thetemperature at 20° C., 70 ml of water was added dropwise and, afterabout an hour of stirring, extracted with 200 ml of toluene. Water (70ml) was added to the organic phase and, after pH adjustment to 9.0 witha 30% aqueous solution of sodium hydroxide, the organic phase wasremoved by phase separation. To the aqueous phase obtained was added 200ml of toluene, the pH was adjusted to 1.0 with 35% aqueous hydrochloricacid, and the aqueous phase was removed by phase separation. The toluenewas distilled off under reduced pressure from the thus-obtained toluenephase to give 21.6 g (116.8 mmol, yield 95%) of(2R)-2-chloro-3-phenylpropionic acid. The optical purity of the productas determined by the same method as in Example 12 was 99.5% ee (R) (rateof configurational inversion 99.5%).

EXAMPLE 16 (2R)-2-Chloro-3-phenylpropionic Acid

[0163] Thionyl chloride (0.18 ml, 2.4 mmol) was added dropwise to asolution of 200 mg (1.2 mmol) of (2S)-2-hydroxy-3-phenylpropionic acid(optical purity 100% ee (S)) in 2 ml of dimethoxyethane at roomtemperature, and the mixture was stirred for 15 hours. To that reactionmixture was added 0.01 ml (0.12 mmol) of pyridine, and the mixture wasstirred at 60° C. for 4 hours. Water (10 ml) was added to the reactionmixture and, after 30 minutes of stirring, the mixture was extractedwith 50 ml of ethyl acetate. The organic phase was washed with 10 ml ofa saturated aqueous solution of sodium chloride and dried over sodiumsulfate. The solvent was distilled off under reduced pressure to give135 mg (yield 61%) of the desired (2R)-2-chloro-3-phenylpropionic acid.The optical purity of the product as determined by the same method as inExample 12 was 97.6% ee (R) (rate of configurational inversion 97.6%).

EXAMPLE 17 (2R)-2-Chloro-3-phenylpropionic Acid

[0164] The reaction was carried out in the same manner as in Example 16using 2 moles of thionyl chloride per mole of the starting materialexcept that the solvents specified below in Table 1 were respectivelyused as the reaction solvent. The results obtained are shown below inTable 1. TABLE 1 Optical purity Configuration Solvent Yield (%) (% ee)inversion rate (%) THF 35 99.4 99.4 1,4-Dioxane 17 99.9 99.9 Toluene 2372.6 72.6 No solvent 20 87 87

EXAMPLE 18 (2S)-2-Acetylthio-3-phenylpropionic Acid

[0165]

[0166] Potassium thioacetate (68 mg, 0.64 mmol) was added to a solutionof 100 mg (0.54 mmol) of the (2R)-2-chloro-3-phenylpropionic acidobtained in Example 14 in 2 ml of dimethylformamide at room temperature,and the mixture was stirred for 24 hours. A 6% aqueous solution ofsodium thiosulfate (0.5 ml) was added to the reaction mixture, and thewhole mixture was extracted with 30 ml of ethyl acetate. The organicphase was washed with 3 ml of 6% sodium thiosulfate aqueous solution, 3ml of water and 3 ml of a saturated aqueous solution of sodium chloride,and dried over sodium sulfate. The solvent was removed under reducedpressure to give 101 mg (yield 83%) of the desired(2S)-2-acetylthio-3-phenylpropionic acid.

[0167]¹H NMR (400 MHz. CDCl₃) δ (ppm): 7.34-7.22 (5H, m), 4.43 (1H, t,J=7.6 Hz), 3.30 (1H, dd, J=13.9 Hz, 7.9 Hz), 3.02 (1H, dd, J=13.9 Hz,7.6 Hz), 2.33 (3H, s).

[0168] The optical purity of the product was determined byderivatization into the corresponding methyl ester by the followingmethod. The product (25 mg, 0.12 mmol) was dissolved in a mixed solventcomposed of 1 ml of methanol and 3.5 ml of toluene, 166 mg (0.15 mmol)of a 10% trimethylsilyldiazomethane solution in hexane was addeddropwise. The reaction was allowed to proceed at room temperature for 30minutes, the solvent was then distilled off under reduced pressure, andthe concentrate was purified on a silica gel column (hexane/ethylacetate=4:1) to give methyl 2-acetylthio-3-phenylpropionate. This methylester was analyzed by HPLC [column: Chiralcel OD-H (product of DaicelChemical Industries), eluent: hexane/isopropanol=100:1, flow rate: 1.0ml/min, temperature; 40° C., detection wavelength: 210 nm, retentiontime: R form 37 min, S form 38 min] and found to have an optical purityof 97.9% ee (S) (configurational inversion rate 98.2%).

EXAMPLE 19 (2S)-2-Acetylthio-3-phenylpropionic Acid

[0169] Potassium thioacetate (93 mg, 0.81 mmol) was added to a solutionof 100 mg (0.54 mmol) of (2R)-2-chloro-3-phenylpropionic acid in 2 ml ofN-methyl-2-pyrrolidone at room temperature, and the mixture was stirredfor 24 hours. The work-up procedure in the same manner as in Example 18of the reaction mixture was followed to give 114 mg (0.51 mmol, yield94%) of the desired (2S)-2-acetylthio-3-phenylpropionic acid.

EXAMPLE 20 (2S)-2-Acetylthio-3-phenylpropionic Acid

[0170] The (2R)-2-chloro-3-phenylpropionic acid obtained in Example 13,20.0 g (108.0 ml), to a mixture of 16.1 g (141.0 mmol) of potassiumthioacetate and 40 ml of dimethylformamide was added dropwise at 0° C.and the mixture was stirred at room temperature for 24 hours. To thereaction mixture were added 60 ml of 6% sodium thiosulfate aqueoussolution and 200 ml of toluene. The mixture was then adjusted to pH 1.7with 35% aqueous hydrochloric acid and, after phase separation, theorganic phase was recovered. This organic phase was washed with 60 ml ofa 6% aqueous solution of sodium thiosulfate, 60 ml of a saturatedaqueous solution of sodium chloride and 60 ml of water. The solvent wasdistilled off under reduced pressure to give 20.7 g (91.8 mmol, yield85%) of the desired (2S)-2-acetylthio-3-phenylpropionic acid. Theoptical purity of the product as determined by the same method as inExample 18 was 98.9% ee (S) (configurational inversion rate 99.1%).

EXAMPLE 21 (2S)-2-Acetylthio-3-phenylpropionic Acid

[0171] The reaction was carried out in the same manner as in Example 18except that the solvents specified below in Table 2 were respectivelyused as the reaction solvent. Based on the integrated area valuesobtained by HPLC analysis for (2S)-2-acetylthio-3-phenylpropionic acid(A) and (2R)-2-chloro-3-phenylpropionic acid (B) after the lapse of eachtime indicated in Table 2, the percentage of(2S)-2-acetylthio-3-phenylpropionic acid (A) as defined by the followingformula 3 was calculated:

Percentage of A (%)=[(HPLC integrated area value for (A))(HPLCintegrated area value for (B)+HPLC integrated area value for (A))]×100

[0172] The results are shown below in Table 2. For evaluating theintegrated values for the above compounds, the following system for HPLCanalysis was used.

[0173] (HPLC)

[0174] [Column: Develosil ODS-HG-3 (product of Nomura Chemical), 150mm×4.6 mm I.D., mobile phase: 0.1% (wt/v) phosphoric acidwater/acetonitrile=75/25, flow rate: 1.0 ml/min, detection: UV 210 nm,column temperature: 40° C., retention time:(2R)-2-chloro-3-phenylpropionic acid (B) 19.9 min,(2S)-2-acetylthio-3-phenylpropionic acid (A) 22.6 min] TABLE 2 SolventAfter 3 hours After 20 hours Water  1% — Methanol  2% — Toluene  0% —Ethyl acetate 36% 92% t-butyl methyl ether Reaction failed to proceeddue to solidification Tetrahydrofuran 32% 93% 1,4-Dioxane 29% 90%Dimethoxyethane 67% 98% Acetonitrile 52% 96% Acetone 79% 97%Dimethylformamide 100%  — N-Methyl-2- 100%  — pyrrolidone

EXAMPLE 22 (2S)-2-Acetylthio-3-phenylpropionic Acid

[0175] The reaction was carried out in the same manner as in Example 18except that the solvents specified below in Table 3 were respectivelyused as the reaction solvent. After the lapse of the time indicated inTable 3, the percentage of (2S)-2-acetylthio-3-phenylpropionic acid asdefined by the above formula 3 was calculated in the same manner as inExample 21. TABLE 3 Solvent After 3 hours Dimethylformamide:t-butylmethyl ether = 2:5 97% (by volume) Dimethylformamide:ethyl acetate = 2:593% (by volume)

INDUSTRIAL APPLICABILITY

[0176] The invention, which has the constitution mentioned above, makesit possible to produce optically active 2-hydroxycarboxylic acids,optically active 2-chlorocarboxylic acids and optically active2-acetylthiocarboxylic acids, which are important in the production ofpharmaceuticals and the like, from readily available starting materialswith high optical purity and high efficiency. It also makes it possibleto isolate or purify optically active 2-hydroxycarboxylic acidsexpediently and efficiently.

1. A method of producing an optically active 2-hydroxycarboxylic acidrepresented by the general formula (1):

wherein R¹ represents a substituted or unsubstituted alkyl groupcontaining 1 to 12 carbon atoms, a substituted or unsubstituted arylgroup containing 6 to 14 carbon atoms or a substituted or unsubstitutedaralkyl group containing 7 to 15 carbon atoms, by reacting an opticallyactive 2-aminocarboxylic acid represented by the general formula (4):

wherein R¹ is as defined above, with a nitrite salt and a protonic acidin aqueous solution, wherein the reaction is carried out by adding thenitrite salt to an aqueous solution containing said optically active2-aminocarboxylic acid and 1 to 3 equivalents, relative to the opticallyactive 2-aminocarboxylic acid, of the protonic acid and having a protonconcentration of 0.5 to 2 mol/kg at a temperature of 10 to 80° C.
 2. Themethod of production according to claim 1, in which R¹ is a benzylgroup, which may be substituted on the aromatic ring.
 3. The method ofproduction according to claim 1 or 2, wherein the proton concentrationis 1 to 2 mol/kg.
 4. The production method according to any of claims 1to 3, wherein the aqueous solution contains 2 to 3 equivalents, relativeto the optically active 2-aminocarboxylic acid (4), of a protonic acid.5. The method of production according to any of claims 1 to 4, whereinthe temperature during nitrite salt addition and during reaction is 15to 60° C.
 6. The method of production according to any of claims 1 to 5,wherein the protonic acid is an inorganic acid.
 7. The method ofproduction according to claim 6, wherein the inorganic acid is sulfuricacid.
 8. The method of production according to any of claims 1 to 7,wherein the nitrite salt is used in an amount of not less than 2 molesper mole of the optically active 2-aminocarboxylic acid (4).
 9. Themethod of production according to any of claims 1 to 8, wherein theaddition rate of the nitrite salt per hour is 0.2 to 1.5 moles per moleof the optically active 2-aminocarboxylic acid (4).
 10. The method ofproduction according to any of claims 1 to 9, wherein the addition ofthe nitrite salt is effected by adding an aqueous solution containingthe same.
 11. A method of crystallizing out an optically active2-hydroxycarboxylic acid represented by the general formula (1):

in which R¹ represents a substituted or unsubstituted alkyl groupcontaining 1 to 12 carbon atoms, a substituted or unsubstituted arylgroup containing 6 to 14 carbon atoms or a substituted or unsubstitutedaralkyl group containing 7 to 15 carbon atoms, which comprises causingcrystallization of the optically active 2-hydroxycarboxylic acid byusing t-butyl methyl ether and a hydrocarbon solvent.
 12. The method ofcrystallization according to claim 11, wherein at least one of anα,β-unsaturated carboxylic acid and an optical isomer each correspondingto the optically active 2-hydroxycarboxylic acid (1) is removed as animpurity.
 13. The method of crystallization according to claim 11 or 12,in which R¹ is a benzyl group, which may be substituted on the aromaticring.
 14. The method of crystallization according to any of claims 11 to13, wherein the volume ratio of t-butyl methyl ether to the hydrocarbonsolvent is 1/20 to
 1. 15. The method of crystallization according to anyof claims 11 to 14, wherein the crystallization is caused by adding ahydrocarbon solvent to t-butyl methyl ether solution containing theoptically active 2-hydroxycarboxylic acid (1) or by adding t-butylmethyl ether solution containing the optically active2-hydroxycarboxylic acid (1) to a hydrocarbon solvent.
 16. The method ofcrystallization according to claim 11 to 15, wherein the hydrocarbonsolvent is an aliphatic hydrocarbon.
 17. The method of crystallizationaccording to claim 16, wherein the aliphatic hydrocarbon is at least onespecies selected from the group consisting of hexane, heptane andmethylcyclohexane.
 18. The method of crystallization according to claim11 to 17, wherein the crystallization is caused at a temperature notlower than 30° C.
 19. The method of crystallization according to any ofclaims 11 to 18, wherein an extract obtained, by using t-butyl methylether, from an aqueous solution containing the optically active2-hydroxycarboxylic acid (1) produced by the method according to any ofclaims 1 to 10, or a concentrate of said extract is subjected to saidmethod of crystallization.
 20. The method according to any of claims 1to 19, wherein the optically active 2-hydroxycarboxylic acid (1) isoptically active 2-hydroxy-3-phenylpropionic acid.
 21. The methodaccording to any of claims 1 to 19, wherein the optically active2-hydroxycarboxylic acid (1) is an optically active2-hydroxy-3-(p-halophenyl)propionic acid.
 22. A method of producing anoptically active 2-chlorocarboxylic acid chloride represented by thegeneral formula (5):

in which R¹ represents a substituted or unsubstituted alkyl groupcontaining 1 to 12 carbon atoms, a substituted or unsubstituted arylgroup containing 6 to 14 carbon atoms or a substituted or unsubstitutedaralkyl group containing 7 to 15 carbon atoms, which comprises reactingan optically active 2-hydroxycarboxylic acid represented by the generalformula (1):

in which R¹ is as defined above, with thionyl chloride and a basiccompound for chlorination with inversion of the configuration at2-position.
 23. A method of producing an optically active2-chlorocarboxylic acid represented by the general formula (2)

in which R¹ represents a substituted or unsubstituted alkyl groupcontaining 1 to 12 carbon atoms, a substituted or unsubstituted arylgroup containing 6 to 14 carbon atoms or a substituted or unsubstitutedaralkyl group containing 7 to 15 carbon atoms, which comprises reactingan optically active 2-hydroxycarboxylic acid represented by the generalformula (1):

in which R¹ is as defined above, by reaction with thionyl chloride and abasic compound for chlorination with inversion of the configuration at2-position and hydrolyzing the thus-obtained optically active2-chlorocarboxylic acid chloride represented by the general formula (5):

in which R¹ is as defined above.
 24. The method of production accordingto claim 22 or 23, wherein the configuration at 2-position in theoptically active 2-hydrocarboxylic acid (1) is (S) and the configurationat 2-position in the optically active 2-chlorocarboxylic acid chloride(5) and in the optically active 2-chlorocarboxylic acid (2) is (R). 25.The method of production according to claim 22 or 23, wherein theconfiguration at 2-position in the optically active 2-hydrocarboxylicacid (1) is (R) and the configuration at 2-position in the opticallyactive 2-chlorocarboxylic acid chloride (5) and in the optically active2-chlorocarboxylic acid (2) is (S).
 26. The method of productionaccording to any of claims 22 to 25, wherein thionyl chloride is used inan amount of not less than 2 moles per mole of the optically active2-hydroxycarboxylic acid (1).
 27. The method of production according toany of claims 22 to 26, wherein at least one selected from among ethersolvents and aromatic hydrocarbon solvents is used as the reactionsolvent for chlorination with inversion of configuration.
 28. The methodof production according to claim 27, wherein at least one speciesselected from the group consisting of tetrahydrofuran, dimethoxyethane,1,4-dioxane and toluene is used as the reaction solvent for chlorinationwith inversion of configuration.
 29. The method of production accordingto any of claims 22 to 28, wherein at least one species selected fromthe group consisting of organic bases, amide group-containing compoundsand quaternary ammonium halides is used as the basic compound.
 30. Themethod of production according to claim 29, wherein at least one speciesselected from the group consisting of pyridine, triethylamine anddiisopropylethylamine is used as the organic base.
 31. The method ofproduction according to claim 29, wherein at least one ofdimethylformamide and N-methyl-2-pyrrolidone is used as the amidegroup-containing compound.
 32. The method of production according toclaim 29, wherein tetra-n-butylammonium chloride is used as thequaternary ammonium halide.
 33. The method of production according toany of claims 22 to 32, wherein the basic compound is used in an amountof not more than 0.5 mole per mole of the optically active2-hydroxycarboxylic acid (1).
 34. The method of production according toany of claims 22 to 33, wherein the rate of configurational inversion inthe step of chlorination with inversion of configuration is not lessthan 95%.
 35. The method of production according to any of claims 22 to34, wherein the optically active 2-hydroxycarboxylic acid represented bythe general formula (1) is obtained by reacting an optically active2-aminocarboxylic acid represented by the general formula (4):

wherein R¹ is as defined above, with a nitrite salt and a protonic acidfor hydroxylation with retention of the configuration at 2-position. 36.The method of production according to claim 35, wherein sodium nitriteis used as the nitrite salt.
 37. The method of production according toclaim 35 or 36, wherein sulfuric acid is used as the protonic acid. 38.The method of production according to any of claims 22 to 37, wherein R¹is a benzyl group.
 39. A method of producing an optically active2-acetylthiocarboxylic acid represented by the general formula (3):

in which R¹ represents a substituted or unsubstituted alkyl groupcontaining 1 to 12 carbon atoms, a substituted or unsubstituted arylgroup containing 6 to 14 carbon atoms or a substituted or unsubstitutedaralkyl group containing 7 to 15 carbon atoms, which comprises reactingan optically active 2-chlorocarboxylic acid represented by the generalformula (2)

in which R¹ is as defined above, with a thioacetate salt forsubstitution by acetylthio group with inversion of the configuration at2-position.
 40. The method of production according to claim 39, whereinthe reaction with the thioacetate salt is carried out in the presence ofan aprotic polar compound.
 41. The method of production according toclaim 40, wherein a nitrogen-containing liquid compound is used as theaprotic polar compound.
 42. The method of production according to claim41, wherein the nitrogen-containing liquid compound is used as a solventand said solvent is an amide group-containing liquid compound.
 43. Themethod of production according to claim 42, wherein at least one speciesselected from the group consisting of dimethylformamide,dimethylacetamide, diethylacetamide, dimethylbutyramide andN-methyl-2-pyrrolidone is used as the amide group-containing liquidcompound.
 44. The method of production according to any of claims 39 to43, wherein the configuration at 2-position in the optically active2-chlorocarboxylic acid (2) is (R) and the configuration at 2-positionin the optically active 2-acetylthiocarboxylic acid (3) is (S).
 45. Themethod of production according to any of claims 39 to 43, wherein theconfiguration at 2-position in the optically active 2-chlorocarboxylicacid (2) is (S) and the configuration at 2-position in the opticallyactive 2-acetylthiocarboxylic acid (3) is (R).
 46. The method ofproduction according to any of claims 39 to 45, wherein an alkali metalthioacetate is used as the thioacetate salt.
 47. The method ofproduction according to claim 46, wherein potassium thioacetate is usedas the alkali metal thioacetate.
 48. The method of production accordingto any of claims 39 to 47, wherein the rate of configurational inversionin the step of substitution by acetylthio group with inversion ofconfiguration is not less than 95%.
 49. The method of productionaccording to any of claims 39 to 48, wherein the optically active2-chlorocarboxylic acid represented by the general formula (2) isproduced by reacting an optically active 2-hydroxycarboxylic acidrepresented by the general formula (1):

wherein R¹ is as defined above, with thionyl chloride and a basiccompound for chlorination with inversion of the configuration at2-position and then hydrolyzing the thus-obtained optically active2-chlorocarboxylic acid chloride represented by the general formula (5):

wherein R¹ is as defined above.
 50. The method of production accordingto claim 49, wherein the thionyl chloride is used in an amount of notless than 2 moles per mole of the optically active 2-hydroxycarboxylicacid (1).
 51. The method of production according to claim 49 or 50,wherein at least one species selected from among ether solvents andaromatic hydrocarbon solvents is used as a reaction solvent for thechlorination with inversion of configuration.
 52. The method ofproduction according to claim 51, wherein at least one species selectedfrom the group consisting of tetrahydrofuran, dimethoxyethane,1,4-dioxane and toluene is used as the reaction solvent for chlorinationwith inversion of configuration.
 53. The method of production accordingto any of claims 49 to 52, wherein at least one species selected fromthe group consisting of organic bases, amide group-containing compoundsand quaternary ammonium halides is used as the basic compound.
 54. Themethod of production according to claim 53, wherein at least one speciesselected from the group consisting of pyridine, triethylamine anddiisopropylethylamine is used as the organic base.
 55. The method ofproduction according to claim 53, wherein at least one ofdimethylformamide and N-methyl-2-pyrrolidone is used as the amidegroup-containing compound.
 56. The method of production according toclaim 53, wherein tetra-n-butylammonium chloride is used as thequaternary ammonium halide.
 57. The method of production according toany of claims 49 to 56, wherein the basic compound is used in an amountof not more than 0.5 mole per mole of the optically active2-hydroxycarboxylic acid (1).
 58. The method of production according toany of claims 49 to 57, wherein the rate of configurational inversion inthe step of chlorination with inversion of configuration is not lessthan 95%.
 59. The method of production according to any of claims 49 to58, wherein the optically active 2-hydroxycarboxylic acid represented bythe general formula (1) is obtained by reacting an optically active2-aminocarboxylic acid represented by the general formula (4):

wherein R¹ is as defined above, with a nitrite salt and a protonic acidfor hydroxylation with retention of the configuration at 2-position. 60.The method of production according to claim 59, wherein sodium nitriteis used as the nitrite salt.
 61. The method of production according toclaim 59 or 60, wherein sulfuric acid is used as the protonic acid. 62.The method of production according to any of claims 39 to 61, wherein R¹is a benzyl group.